title: Hesperetin, a potential therapy for carcinoid cancer.
abstract: BACKGROUND
  The investigators' laboratory has demonstrated that the Notch1 signaling pathway acts as a tumor suppressor in carcinoid tumors. The aim of this study was to examine hesperetin, a flavonoid, as a potential Notch1 activator and carcinoid tumor suppressor.
  
  
  METHODS
  A high-throughput drug screen revealed hesperetin as a Notch1 activator. Human gastrointestinal carcinoid (BON) cell growth after hesperetin treatment was assessed with a 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay. Western blots were used to measure neuroendocrine tumor markers, human achaete-scute complex-like 1, and chromogranin A. Notch1 expression was measured using western blot analysis and real-time polymerase chain reaction.
  
  
  RESULTS
  Hesperetin induced cell death in a dose-dependent manner and reduced achaete-scute complex-like 1 and chromogranin A expression, with a concomitant rise in Notch1 levels. It also induced Notch1 messenger ribonucleic acid, indicating regulation at the transcriptional level.
  
  
  CONCLUSIONS
  Hesperetin induces Notch1 expression in carcinoid cells, subsequently suppressing tumor cell proliferation and bioactive hormone production. This provides evidence for further study into hesperetin as a potential treatment for carcinoid cancer.
authors.affiliation: Department of Surgery, University of Wisconsin, Madison, WI, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Zarebczan
authors.forename: Scott N
authors.initials: SN
authors.lastname: Pinchot
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Kunnimalaiyaan
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000097:blood; D015153:Blotting, Western; D002276:Carcinoid Tumor / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006569:Hesperidin / Q000494:pharmacology*; D006801:Humans; D016133:Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D006569:Hesperidin; C013015:hesperetin